( A–B) Dose dependent shifts in the ( A) voltage dependence of activation (ΔV 0.5) and ( B) changes in maximal conductance (G max) for Kv7.1/KCNE1 induced by Lin-glycine (black squares n = 4 mean ± SEM), Pin-glycine (red circles n = 3 mean ± SEM), and DHA-glycine (green triangles n = 4 mean ± SEM). Structures for PUFA analogues with glycine head group: Lin-glycine, Pin-glycine, and DHA-glycine (top). See Figure 4-figure supplements 1–6 for more details. ( E–F) Dose dependent shifts in the ( E) voltage dependence of inactivation (ΔV 0.5) and ( F) changes in maximal conductance (G max) for Nav1.5/β1 induced by Lin-taurine (black squares n = 3 mean ± SEM), N-AT (red circles n = 3 mean ± SEM), Pin-taurine (green triangles n = 4 mean ± SEM), and DHA-taurine (blue triangles n = 3 mean ± SEM). ( C–D) Dose dependent shifts in the ( C) voltage dependence of inactivation (ΔV 0.5) and ( D) changes in maximal conductance (G max) for Cav1.2/β3/α2δ induced by Lin-taurine (black squares n = 3 mean ± SEM), N-AT (red circles n = 3 mean ± SEM), Pin-taurine (green triangles n = 5 mean ± SEM), and DHA-taurine (blue triangles n = 3 mean ± SEM). ( A–B) Dose dependent shifts in the ( A) voltage dependence of activation (ΔV 0.5) and ( B) changes in maximal conductance (G max) for Kv7.1/KCNE1 induced by Lin-taurine (black squares n = 3 mean ± SEM), N-AT (red circles n = 5 mean ± SEM), Pin-taurine (green triangles n = 4 mean ± SEM), and DHA-taurine (blue triangles n = 3 mean ± SEM). Structures for PUFA analogues with taurine head groups: Lin-taurine, N-AT, Pin-taurine, and DHA-taurine (top). Our data suggest that PUFA analogues could potentially be developed as therapeutics for LQTS and cardiac arrhythmia.Ĭav1.2 Long QT Syndrome Nav1.5 Xenopus oocytes iks molecular biophysics none polyunsaturated fatty acids structural biology. In addition, a PUFA analogue selective for the cardiac I Ks channel (Kv7.1/KCNE1) is effective in shortening the cardiac action potential in human-induced pluripotent stem cell-derived cardiomyocytes. The effects of specific PUFA analogues range from selective for a specific ion channel to broadly modulating cardiac ion channels from all three families (Na V, Ca V, and K V). Here we demonstrate that PUFA analogues vary in their selectivity for human voltage-gated ion channels involved in the ventricular action potential. Polyunsaturated fatty acids (PUFAs) have emerged as potential therapeutics for LQTS because they are modulators of voltage-gated ion channels. Mutations in these channels can cause Long QT Syndrome (LQTS) which increases the risk for ventricular fibrillation and sudden cardiac death. The cardiac ventricular action potential depends on several voltage-gated ion channels, including Na V, Ca V, and K V channels.
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